OxiranEcarboxylic acids for the treatment of diabetes

ABSTRACT

The invention relates to novel arylalkyl- or aryloxyalkyl-substituted oxiranecarboxylic acids of the general formula I                    
     in which Ar, R 3 , Y and n are as defined in the description, and also to medicaments comprising them and to their use for the treatment and prophylaxis of the disorders mentioned in claim  4  which are caused by disturbances of glucose and/or lipid metabolism, such as, for example, diabetes type 2 and other insulin-resistant conditions.

AREA OF APPLICATION OF THE INVENTION

The invention relates to novel arylalkyl- or aryloxylalkyl-substitutedoxiranecarboxylic acids, to processes for their preparation, to theiruse and to medicaments comprising them.

PRIOR ART

EP 0 046 590 describes hypoglycaemically and hypoketonaemically activephen(alk)oxy-substituted oxiranecarboxylic acids and esters thereof ofthe general formula A

in which

R¹ is a hydrogen atom, a halogen atom, a 1-4 C-lower alkyl group, a 1-4C-lower alkoxy group, a nitro group or a trifluoromethyl group,

R² has one of the meanings of R¹,

R³ is a hydrogen atom or a 1-4 C-lower alkyl group,

Y is the grouping —O—(CH₂)_(m)—,

m is 0 or an integer from 1 to 4 and

n is an integer from 1 to 8,

where the sum of m and n is an integer from 2 to 8, and

the salts of the carboxylic acids.

EP 0 231 367 B1 describes the use of the compounds of the generalformula A for the prevention and/or treatment of disorders which arecaused by an elevated concentration of cholesterol and/or triglyceridein the organism.

DE-A 4 340 879 A1 describes the use of the compounds of the generalformula A in the prevention and/or treatment of cardiac insufficiency.

DE-A 3 032 668 describes, inter alia, non-aromaticcycloalkyl(alk)oxy-substituted oxirane-carboxylic acids.

EP 0 283 168 describes phenylalkyl- and phenoxyalkyloxiranecarboxylicacids and esters thereof having 1-2 fluorine substituents in the alkylchain which are said to act as inhibitors of fatty acid oxidation with alow potential to cause damage to cardiac muscle function.

DESCRIPTION OF THE INVENTION

The invention provides novel arylalkyl- or aryloxyalkyl-substitutedoxiranecarboxylic acids or pharmacologically acceptable salts thereof ofthe general formula I

in which

Ar is a substituted phenyl radical

 a 1- or 2-naphthyl radical which unsubstituted is substituted by aradical R⁴ or is a heterocyclic radical Het,

R¹ is a hydrogen atom, a halogen atom or a 1-4 C-lower alkyl group,

R² is one of the groups

 or a fully or predominantly fluorine-substituted 1-3 C-alkoxy group,

R³ is a hydrogen atom or a 1-4 C-lower alkyl group,

R⁴ is a hydrogen atom, a 1-4 C-lower alkyl group, an optionally fully orpredominantly fluorine-substituted 1-3 C-alkoxy group or a halogen atom,

R5 in a 1-4 C-lower alkyl group,

Y is the grouping —O— or —CH₂—,

n is an integer from 2 to 8 and

Het is a heterocyclic ring, which preferably has 5 members and isselected from the group consisting of thiophene, thiazole, isothiazole,pyrrole and, particularly preferably, pyrazole, and which may carry 1 or2 identical or different substituents R¹,

where the chain —(CH₂)_(n)— may optionally be interrupted by a —CH(CH₃)—or —C(CH₃)₂— unit, and the salts of the corresponding carboxylic acids(R³═H).

The 1-4 C-lower alkyl radicals can be straight-chain or branched.Straight-chain alkyl radicals are, for example, the methyl, ethyl,n-propyl and the butyl radical, of which those having 1 to 2 carbonatoms are preferred. Branched alkyl radicals are, for example, theisopropyl, isobutyl and the sec-butyl radical, of which that having 3carbon atoms is preferred. Suitable alkyl radicals of lower alkoxygroups are both straight-chain and branched lower alkyl groups. Apreferred lower alkyl group is the methoxy group. Suitable alkylradicals in acyl groups are both straight-chain and branched lower alkylgroups, of which the methyl group and the tert-butyl group arepreferred.

Halogen atoms are fluorine, chlorine and bromine atoms, of whichfluorine and, in particular, chlorine, are preferred.

In the substituted phenyl radicals Ar, the substituents R¹ and R² arepreferably in the m- or p-position and R¹ is preferably a hydrogen atom.

Among the fully or predominantly fluorine-substituted 1-3-C-alkoxygroups, preference is given to the trifluoromethoxy, the2,2,2-trifluoroethoxy, the 1,1,2,2-tetrafluoroethoxy group and inparticular to the difluoromethoxy group.

Suitable salts are salts with inorganic and organic bases.Pharmacologically unacceptable salts are converted, by methods known perse, into pharmacologically, i.e. biologically, acceptable salts, whichare preferred from among the salts according to the invention. Suitablecations for use for salt formation are, in particular, the cations ofthe alkali metals, alkaline earth metals or noble metals; however, it isalso possible to use the corresponding cations of organic nitrogenbases, such as amines, aminoalcohols, amino sugars, basic amino acids,etc.

Examples which may be mentioned are salts of lithium, sodium, potassium,magnesium, calcium, aluminium, ethylenediamine, dimethylamine,diethylamine, morpholine, piperidine, piperazine, N-lower alkylpiperazine (for example N-methylpiperazine), methycyclohexylamine,benzylamine, ethanolamine, diethanolamine, triethanolamine,tris-(hydroxymethyl)-aminomethane, 2-amino-2-methylpropanol,2-amino-2-methyl-1,3-propanediol, glucamine, N-methylglucamine,glucosamine, N-methylglucosamine, lysine, ornithine, arginine,quinoline.

The arylalkyl- or aryloxyalkyloxiranecarboxylic acids of the generalformula I according to the invention have a chiral centre. Accordingly,the invention includes both the racemates and the enantiomers -andmixtures thereof. For racemate separation of the carboxylic acids,particular preference is given to using salts with optically activebases, such as cinchonidine or dehydroabietylamine.

The compounds according to the invention have useful pharmacologicalproperties which make them. They have hypoglycaemic and lipid-loweringaction and improve the efficacy of insulin in the treatment ofinsulin-resistant conditions, such as, for example, in the case ofmetabolic syndrome and, in particular, diabetes type 2.

They are superior to the known oxiranecarboxylic acids of the prior artin the following manner:

a) they are distinguished by a therapeutic index which is significantlybetter under certain conditions in the manner that the increases ofliver enzymes (transaminases) which occur in individual type 2-diabeticsoccur to a considerably lesser extent, if at all,

b) they have superior action with respect to increasing the effect ofinsulin in insulin-resistant conditions,

c) they are metabolized more quickly and do not form any long-lastingmetabolites.

Owing to their advantageous and superior efficacy, the compounds of thegeneral formula I according to the invention and the pharmacologicallyacceptable salts are suitable for the treatment and prophylaxis ofdisorders which are caused by disturbances of glucose and lipidmetabolism, in human and veterinary medicine.

They are employed, for example, for treating prediabetic conditions; forthe treatment and prevention of the manifestation of diabetes type 2 andof all pathological conditions which are associated with pathologicalinsulin resistance; for the treatment and prevention of themanifestation of all pathological conditions with pathologicallyelevated production of ketone bodies; for the treatment and preventionof the manifestation of all pathological conditions which are caused byelevated cholesterol and/or triglyceride concentrations in the blood(hyperlipidaemia, arteriosclerosis, coronary heart disease)

The invention also provides the compounds according to the invention foruse in the treatment and prophylaxis of the disorders mentioned.

The invention furthermore provides medicaments comprising one or morearylalkyl- or aryloxyalkyloxiranecarboxylic acids of the general formulaI

in which

Ar is a substituted phenyl radical

 a 1- or 2-naphthyl radical which is substituted by a radical R⁴ or is aheterocyclic radical Het,

R¹ is a hydrogen atom, a halogen atom or a 1-4 C-lower alkyl group,

R² is one of the groups

 or a fully or predominantly fluorine-substituted 1-3 C-alkoxy group,

R³ is a hydrogen atom or a 1-4 C-lower alkyl group,

R⁴ is a hydrogen atom, a 1-4 C-lower alkyl group, an optionally fully orpredominantly fluorine-substituted 1-3 C-alkoxy group or a halogen atom,

R⁵ is a 1-4 C-lower alkyl group,

Y is the grouping —O— or —CH₂—,

n is an integer from 2 to 8 and

Het is a heterocyclic ring, which preferably has 5 members and isselected from the group consisting of thiophene, thiazole, isothiazole,pyrrole and, particularly preferably, pyrazole, and which may carry 1 or2 identical or different substituents R¹,

where the chain —(CH₂)_(n)— may optionally be interrupted by a —CH(CH₃)—or —C(CH₃)₂— unit, and the pharmacologically acceptable salts of thecarboxylic acids (R³═H) with inorganic or organic bases.

Moreover, the invention provides the use of the compounds according tothe invention for preparing medicaments for controlling the disordersmentioned.

The medicaments are prepared by processes known per se. As medicaments,the compounds according to the invention are employed either as such or,if appropriate, in combination with suitable pharmaceutical excipients.If the pharmaceutical preparations comprise pharmaceutical excipients inaddition to the active compounds, the active compound content of thismixture is from 1 to 95, preferably from 10 to 85% (w/w) of the totalmixture. The medicaments are formulated in suitable doses, for examplefor oral or parenteral (intravenous, intramuscular) administration. Thedaily dose for oral administration in humans is generally between 0.1and 30, preferably between 0.3 and 15, in particular between 0.6 and 3mg/kg of body weight. The dosage for parenteral treatment is between 0.3and 1 mg of active compound/kg of body weight.

The pharmaceutical preparations preferably comprise the active compoundsaccording to the invention and non-toxic, pharmaceutically acceptablepharmaceutical excipients which are employed as additive or diluent insolid, semi-solid or liquid form or as coating material, for example inthe form of a capsule, a tablet coating, a bag or another container forthe therapeutically active component. An excipient may serve, forexample, to mediate the uptake of the medicament by the body, asformulation auxiliary, as sweetener, as taste corrigent, as colorant oras preservative.

In addition to the compounds of the general formula I, according to theinvention in which the substituents are as defined above, and/or theirsalts, the pharmaceutical preparations may furthermore comprise one ormore pharmacologically active components of other medicament groups,such as antidiabetics (sulphonamides, sulphonylureas,thiazolidinediones, etc.) or hypolipidemics (nicotinic acid and itsderivatives, clofibrate, HMG-CoA reductase inhibitors).

The compounds according to the invention are prepared by processes knownper se. Detailed instructions for preparing the principal compound classare described in EP 0046 590 equivalent to Eistetter et al., U.S. Pat.No. 4,337,267, the disclosure of which is incorporated herein byreference mentioned at the outset, which is incorporated into thedisclosure of this application with respect to process technique. Theseprocedures can be applied, in analogous process steps, to the novelcompounds according to the invention. For the person skilled in the art,it is possible without problems to introduce the novel meaningsaccording to the invention for the radical R², which are chemicallycustomary per se, in comparison to the European Application mentioned,by numerous standard methods.

Here, the compounds of the general formula I are usually obtained in theform of racemic mixtures, which are separated into the enantiomers usingknown methods. For example, the racemate is converted into diasteromersusing an optically active resolving agent, and the diastereomers aresubsequently separated by selective crystallization and converted intothe corresponding optical isomers. Optically active resolving agentswhich can be employed are, for example, optically active bases, such as1- and d-1-phenylethylamine, cinchonidine or d-ephedrine, which are usedto prepare salts of the acids of the general formula I, or opticallyactive alcohols, such as borneol or menthol, which are used to prepareesters from the acids of the general formula I. Racemate resolution ofthe acids using dehydroabiethylamine as salt former has been found to beparticularly suitable.

The Examples below are intended to illustrate the invention in moredetail, without limiting it.

EXAMPLE 1

The compounds of the formula I according to the invention lower theglucose concentration in the blood of rats which have been madeinsulin-resistant by prolonged fasting. In this action, the saidcompounds are superior to the active compounds known from the prior art,for example rac-etomoxir (see EP 046 590).

In the Table below, the representative substances which were examinedare numbered for identification:

Number Name of the compound 1 Ethyl 2-(6-(4-chlorophenoxy)hexyl)oxi-rane-2-carboxylate 2 Ethyl 2-(6-(4-difluoromethoxy-phenoxy)hexyl)oxirane-2-carboxylate 3 Ethyl 2-(5-(4-difluoromethoxyphenoxy)pentyl)oxirane- 2-carboxylate 4 Ethyl2-(5-(4-acetylphenoxy)pentyl)oxi- rane-2-carboxylate

In Table 1, the following findings are shown:

In Column A The blood glucose-lowering effect of the representativesubstances in insulin-resistant rats (after 24 hour fasting) 2 hoursafter oral administration of equimolar doses (100 μmol/kg of bodyweight)

In Column B The triglyceride-lowering effect of the representativesubstances in the blood plasma of fed, healthy rats after oraladministration of equimolar doses (100 μmol/kg of body weight) for 16days, 24 hours after the last administration of substance,

In Column C The cholesterol-lowering effect of the representativesubstances in the blood plasma of fed, healthy rats after oraladministration of equimolar doses (100 μmol/kg of body weight) for 16days, 24 hours after the last administration of substance.

What is stated are the changes in per cent of the animals which havebeen treated with substance, compared to control animals which weretreated with placebo, calculated from the mean values of in each case 10individual values.

TABLE 1 Substance (A) (B) (C) No. Glucose (%) Triglycerides (%)Cholesterol (%) 1 −18 −50 −15 2 −27 −69 −13 3 −27 −73 −26 4  −7 −41  −8

The superiority of the compounds according to the invention compared tothe prior art with respect to lowering glucose after fasting, chosen asan experimental model of insulin resistance, is particularly pronouncedin the case of the substances No. 2 and 3 in Tab. 1. Taking into accountthe triglyceride- and cholesterol-lowering effect, substance No. 3 inparticular has an effect which is superior to the prior art.

EXAMPLE 2

Table 2 shows the influence of the representative substances onundesirable side effects which have been described in the scientificliterature (K. Ratheiser, B. Schneeweiss et al.: Metabolism Clin. Exp.40 (1991) 1185; H. P. O. Wolf in C. J. Bailey & P. R. Flatt, Newantidiabetic drugs, Smith-Gordon, London 10 1990):

In Column A The transient increase in the activity of the liver enzymeglutamic-pyruvate tranzamindse (GFT) in the blood plasma after oraladministration of equimolar doses of the substances to healthy, fed ratsfor 16 days, 24 hours after the last administration of substance,

In Column B The increase of the relative weight of the heart (weight ofthe heart/100 g of body weight) as an indication of cardiac hypertrophyafter oral administration of equimolar doses of the substances tohealthy, fed rats for 16 days, 24 hours after the last administration ofsubstance,

In Column C The pharmacological safety index, calculated from thelowering of the blood concentrations ofglucose+triglycerides+cholesterol in per cent divided by the increase ofGPT activity+relative weight of the heart in per cent.

TABLE 2 (B) (A) Relative weight of (C) Substance GPT activity the heartSafety index No. (%) (%) (%) 1 8 14 3.77 2 5 14 5.74 3 12  11 5.48 4−9   −2 56

The higher the index, the greater the safety of the substance. In thisrespect, the substance No. 4 is distinguished in that it is particularlysuperior to the prior art. The substances No. 2 and 3 are likewisesuperior to the prior art.

EXAMPLE 3 Test Animals

The test animals used were male Sprague-Dawley rats from the SPF breedIvanovas (Kisslegg, Germany) having a body mass of 255-400 g. Theanimals were kept in a conventional manner, 4 animals each in cages madeof Makrolon (22×38 cm) in a climatized room (21-23 degrees Celcius) witha fixed day/night rhythm (7 a.m/7 p.m) and a regulated relativeatmospheric humidity of 55-60%. The animals received a maintenancediet—Altromin 1320 from Altromin (Lage, Germany)—and water ad libitum.

To determine the effect of the substance on blood glucose, feed waswithdrawn 24 hours before the administration of the substance to producean insulin-resistant condition.

The animals were divided at random in 5 groups of 10 animals each andmarked. The substances were administered to the animals in the form of aneutral, aqueous emulsion (1 part by weight of substance+2 parts byweight of Cremophor EL—an emulsifier from BASF AG, Germany) in a volumeof 10 ml/kg of body weight using a stomach tube.

EXAMPLE 4 Preparation of Blood and Serum

To determine the glucose in the blood, 50 μl of blood were collectedfrom the retrobulbular venousplexus 2 hours after the administration ofthe substance, using a glass capillary, from animals which had beenfasting for 24 hours, and the blood was deproteinated in ice-coldperchloric acid (0.66 mol/l).

After centrifugation, the glucose was determined in the supernatantusing enzymatic standard methods.

To determine the parameters triglycerides, cholesterol and the activityof the glutamic-pyruvic transaminase (GPT), blood plasma was used. Theblood plasma was obtained as an erythrocyte-free supernatant minutesafter venous blood sampling into heparinized Eppendorf reaction vesselsby centrifugation (2×2 minutes at 16,000 rpm in an Eppendorfcentrifuge).

EXAMPLE 5 Analytical Methods

Glucose: Enzymatic test with hexokinase/glucose-6-phosphatase, testcombination from Boehringer Mannheim, Germany.

Triglycerides: Enzymatic test with lipase/glycerokinase, testcombination from Boehringer Mannheim, Germany.

Cholesterol: Enzymatic colour test (CHOD-PAP method), test combinationfrom Boehringer Mannheim, Germany.

GPT: Kinetic enzyme test, test combination from goehringer Mannheim,Germany.

Relative weight The animals were killed by decapitation of the heart:and exsanguination, and the weight of the heart muscle, which had beenfreed from the right atrium, was determined by weighing and based on 100g of body weight.

What is claimed is:
 1. Compounds of the formula I

in which Ar is a substituted phenyl radical

 a 1- or 2-naphthyl radical which is substituted by a radical R⁴, R¹ isa hydrogen atom, halogen atom or a 1-4 C-lower alkyl group, R² is one ofthe groups

 or a fully or predominantly fluorine-substituted 1-3 C-alkoxy group, R³is a hydrogen atom, a 1-4 C-lower alkyl group, R⁴ is a hydrogen atom, a1-4 C-lower alkyl group, an optionally fully or predominantly fluorinesubstituted 1-3 C-alkoxy group or a halogen atom, R⁵ is a 1-4 C-loweralkyl group, Y is a grouping —O— or —CH₂—, n is an integer from 2 to 8and where the chain —(CH₂)_(n)— may optionally be interrupted by a—CH(CH₃)— or —C(CH₃)₂— unit, and the salts of the carboxylic acids(R³═H).
 2. The compound of formula I according to claim 1 wherein thecompound is selected from the group consisting of ethyl2-(6-(4-difluoromethoxyphenoxy) hexyl)oxirane-2-carboxylate, ethyl2-(5-(4-difluoromethoxyphenoxy) pentyl)oxirane-2-carboxylate , ethyl2-(5-(4-acetylphenoxy)pentyl)oxirane-2-carboxylate or mixtures thereof.3. The compound of formula I according to claim 1 wherein the compoundis ethyl 2-(5-(4-acetylphenoxy)pentyl)oxirane-2-carboxylate.
 4. Thecompound of formula I according to claim 1 wherein the compound is ethyl2-(6-(4-difluoromethoxyphenoxy)hexyl)oxirane-2-carboxylate.
 5. Thecompound of formula I according to claim 1 wherein the compound is ethyl2-(5-(4-difluoromethoxyphenoxy)pentyl)oxirane2-carboxylate.
 6. Apharmaceutical preparation comprising one or more compounds of formula Iaccording to claim 1 together with a pharmaceutically acceptableexcipients and/or auxiliaries.
 7. The pharmaceutical preparationaccording to claim 6 wherein the compound is selected from the groupconsisting of ethyl 2-(6-(4-difluoromethoxyphenoxy)hexyl)oxirane-2-carboxylate, ethyl 2-(5-(4-difluoromethoxyphenoxy)pentyl)oxirane-2-carboxylate, ethyl2-(5-(4-acetylphenoxy)pentyl)oxirane-2-carboxylate or mixtures thereof.8. The phaimaoical preparation according to claim 7 wherein the compoundis ethyl 2-(5-(4-acetylphenoxy)pentyl)oxirane-2-carboxylate.
 9. Thepharmaceutical preparation according to claim 7 wherein the compound isethyl 2-(6-(4-difluoromethoxyphenoxy)hexyl)oxirane-2-carboxylate. 10.The pharmaceutical preparation according to claim 7 wherein the compoundis ethyl 2-(5-(4-difluoromethoxyphenoxy)pentyl)oxirane-2 caroxylate. 11.A method for treating disorders caused by disturbances of glucose and/orlipid metabolism comprising the steps of: a) providing the compound ormixture of compounds of formula I according to claim 1; and b)administering an effective amount of the compound or mixture ofcompounds to an animal in need of such a treatment.
 12. The methodaccording to claim 11 wherein the compound is selected from the groupconsisting of ethyl2-(6-(4-difluoromethoxyphenoxy)hexyl)oxirane-2-carboxylate, ethyl2-(5-(4-difluoromethoxyphenoxy) pentyl)oxirane-2-carboxylate, ethyl2-(5-(4-acetylphenoxy)pentyl)oxirane-2-carboxylate or mixtures thereof.13. The method according to claim 12 wherein the compound is ethyl2-(5-(4-acetylphenoxy)pentyl)oxirane-2-carboxylate.
 14. The methodaccording to claim 11 wherein the disorder is elevated glucose.
 15. Themethod according to claim 11 wherein the disorder is elevatedtriglyceride.
 16. The method according to claim 11 herein the disorderis elevated cholesterol.
 17. The method according to claim 11 whereinthe disorder is glucose metabolism and the compound is selected from thegroup consisting of ethyl2-(6-(4-difluoromethoxyphenoxy)hexyl)oxiane-2-cartoxylate, ethyl2-(5-(4-difluoromethoxyphenoxy)pentyl)oxirane-2-carboxylate or mixturesthereof.
 18. The method according to claim 11 wherein the disorder islipid metabolism and the compound is ethyl2-(5-(4-difluoromethoxyphenoxy)pentyl)odrane-2-carboxylate.
 19. Themethod according to claim 11 wherein the disorder is selected from thegroup consisting of pathological glucose tolerance, prediabetes,diabetes type 2, conditions with insulin resistance, conditions withpathologically elevated production of ketone bodies, hyperlipidaemia,arteriosclerosis and/or coronary heart disease.